Premature surgical menopause increases the lifetime risk of cognitive decline and dementia. The objective of the current study is to elucidate the mechanisms that underlie these increased neurological risks following surgical menopause. Our central hypothesis is that the premature loss of 17?-Estradiol (E2) after surgical menopause leads to hypoxia of the forebrain due to a loss of neuron-derived hemoglobin-alpha (Hb-?). We further hypothesize that the ER coregulator, PELP1 plays an essential role to protect the forebrain from neurodegeneration and dementia. We will use the following specific aims to test our hypotheses. Aim 1 will determine the role and regulation of local-derived Hb-? in the forebrain. We will determine whether: 1a. Loss of Hb-? and enhanced forebrain hypoxia after long-term gonadectomy is gender-specific and only occurs in females, 1b. E2 replacement prevents the surgical menopausal-induced loss of Hb-? and cortical and hippocampal hypoxia in a PELP1-dependent manner, 1c. Attenuated expression of local-derived Hb-? will lead to hypoxia of forebrain neurons and increased ROS/oxidative stress-induced neuronal damage, 1d. Decreased levels of local-derived Hb-? will lead to Hif-1? induced pro-apoptotic signaling and enhanced sensitivity of forebrain neurons to damage by stressors, such as ischemia and ?-amyloid. Aim 2 will determine the role of PELP1 in regulation of forebrain neuroinflammation, A? processing and cognitive function. Using a forebrain KO mouse model, we will test whether forebrain deletion of PELP1 will lead to: 2a. Enhanced hypoxia, gliosis and neuroinflammation in the forebrain, 2b. Increased oxidative stress and neuronal damage, 2c. Induction of amyloidogenic A? processing, Tau hyper-phosphorylation, and cognitive decline, and 2d. Alteration in expression of survival and developmental genes via epigenetic mechanisms. Aim 3 will examine relationships of human brain Hb-? expression, cognition, and AD pathology, in deceased and autopsied women with and without surgical menopause. We hypothesize that: 3a. Women who had surgical menopause, compared to those with natural menopause, will have lower expression of neuronal- derived Hb-? (and in secondary analysis, PELP1) in postmortem brain tissue; 3b. Lower expression of Hb- ? (and PELP1) in women with surgical menopause will be associated with higher levels of AD pathology, and in secondary analysis with neuritic plaques in particular; and 3c. Lower expression of Hb-? (and PELP1) in women with surgical menopause will be associated with lower levels of cognitive function, and in secondary analysis with memory in particular. The proposed research is innovative in proposing that E2 regulates local Hb-? to modulate neuronal oxygenation, the utilization of a novel forebrain-specific PELP1 KO mouse model, and the use of human brain samples and cognitive data to extend the findings to the human. The studies will have a significant impact by elucidating how surgical menopause leads to increased risks of cognitive decline and dementia.